ERCC1、TS、GST-π在胃印戒细胞癌与普通腺癌中的表达及其临床意义
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摘要
背景与目的
胃癌是我国常见的消化系肿瘤,严重威胁人类健康。就发病率和死亡率而言,胃癌在我国居恶性肿瘤第二位,治疗原则以手术为主,但是往往在原发肿瘤出现明显症状之前已出现了播散性转移,故多数患者已失去手术机会,而选择以化疗为主的综合治疗。
胃印戒细胞癌是胃癌的一种特殊病理类型,是多发于中青年的高度恶性肿瘤之一,在原发性胃癌中占有一定比例。胃印戒细胞癌无特异性临床表现,临床上易误诊,就诊时大多已属中晚期,有广泛侵袭和转移,特别是难以控制的远处脏器转移,且对放化疗均不敏感,预后极差,其自然病程仅为3～6个月。胃印戒细胞癌是一类分化差,侵袭力强、多在胃壁内弥漫浸润性生长、进展速度快、易转移、临床表现无特异性、不易早期诊断且预后较差的一类高度恶性肿瘤。因此,其特殊的临床特点、生物学特征与行为、治疗及其预后等倍受人们关注。
常用于治疗胃癌的化疗药物有5-氟尿嘧啶(5-fluorouracil,5-Fu)、阿霉素(Adriamycin,ADM)、顺铂(Cisplatin,DDP)、奥沙利铂(Oxaliplatin,L-OHP)、伊立替康(Irinotecan,CPT-11)、依托泊苷(Etoposide,VP-16),氨甲喋吟(Methotrexate,MTX),紫杉类(Paclitaxel、Docetaxel)等,其中铂类与5-Fu的联合化疗方案,是胃癌化疗最常用的方案。然而肿瘤原发或继发性对化疗药物不敏感常常影响化疗效果,是临床常见而又难以解决的问题之一。切除修复交叉互补基因(ERCC1)、胸苷酸合成酶(TS)、谷胱甘肽S转移酶(GST-π)是与胃癌治疗及预后密切相关的三个指标。已有资料显示胃癌组织ERCC1高表达与以L-OHP、DDP为基础的化疗疗效负相关,而对未接受化疗者,ERCC1高表达是有益于生存期的指标,但ERCC1与生存期的关系仍存在争议;胃癌组织中TS表达与氟尿嘧啶(5-Fu)耐药之间仍存在争议,大多数研究认为TS过表达与5-Fu耐药正相关,与生存期负相关,是胃癌不良预后指标,但也有研究认为原发灶TS的表达情况不能预测晚期胃癌以5-Fu为基础化疗的疗效;有研究显示GST-π可能作为胃癌早期诊断的一项指标,GST-π阳性的胃癌患者不仅对DDP,而且对阿霉素、5—Fu、丝裂霉素、卡铂的敏感性均低,表明GST-π对肿瘤产生多药耐药性起重要作用。本文拟通过观察ERCC1,TS,GST-π在胃印戒细胞癌与普通腺癌中的表达情况,研究ERCC1,TS,GST-π在胃印戒细胞癌与普通胃腺癌中的表达水平的区别及其临床意义,为今后胃印戒细胞癌与普通腺癌的化疗方案的选择提供依据。
方法
采用回顾性分析,应用免疫组织化学染色方法(S-P法),使用特异性ERCC1、TS、GST-π抗体,检测61例胃印戒细胞癌标本和60例普通胃腺癌标本中ERCC1、TS、GST-π三种抗原的表达情况,用SPSS13.0软件包分析它们在胃印戒细胞癌与普通腺癌中表达的差异,以及它们与胃印戒细胞癌及腺癌临床病理特征的关系,进而推测它们与胃印戒细胞癌及腺癌治疗敏感性及预后的关系。
结果
在肿瘤细胞中,ERCC1定位于细胞核,TS定位于细胞浆/核,以细胞浆中表达为阳性,GST-π主要定位于细胞浆中,部分细胞核也有表达,以细胞浆表达为阳性。在61例胃印戒细胞癌病理标本中,ERCC1表达阳性率为25.59%(15/61),TS表达阳性率为19.67%(12/61),GST-π表达阳性率为54.10%(33/61)。在60例胃腺癌病理标本中,ERCC1表达阳性率为26.17%(16/60),TS表达阳性率为38.33%(23/60),GST-π表达阳性率为71.67%(43/60)。二者ERCC1阳性率差异无显著性意义(P＞0.05),TS、GST-π阳性率差异有显著性意义(P＜0.05)。在印戒细胞癌患者中,ERCC1、TS、GST-π的表达与患者的性别、年龄、饮酒、病理分期、淋巴结转移数目无显著性差异(P＞0.05),ERCC1、GST-π的表达与浸润深度的差别有统计学意义(P＜0.05)。在普通腺癌患者中,ERCC1、TS、GST-π的表达与患者的性别、年龄、饮酒、病理分期、淋巴结转移数目、浸润深度、分化程度无显著性差异(P＞0.05)。在深层浸润(T3-T4)的患者中,TS、GST-π的表达在印戒细胞癌与腺癌中的差异有显著性(P＜0.05)。
结论
1.ERCC1的表达在印戒细胞癌与普通腺癌中无明显差别,TS、GST-π在印戒细胞癌中的表达水平明显低于普通腺癌。
2.ERCC1、TS、GST-π的表达与患者的性别、年龄、饮酒、病理分期、淋巴结转移数目无关。
3.印戒细胞癌中ERCC1、GST-π的表达与浸润深度有关,浸润深度越浅ERCC1、GST-π表达率越高;普通腺癌中ERCC1、TS、GST-π的表达均与浸润深度无关。
4.在深层浸润(T3-T4)患者中,印戒细胞癌中TS、GST-π的表达明显低于胃普通腺癌。
BACKGROUND AND OBJECTIVE:Gastric carcinoma is a common gastrointestinal carcinoma in our country,which threatens the human health seriously,and its mobility and mortality ranks the second in all kinds of the malignant tumor.The treatment principle is the surgery primarily,but usually it metabasis before dignosis,therefore most has lost the surgery opportunity,and chose the chemotherapy based complex therapy.
Gastric signet ring cell carcinoma is a special pathological type of the gastric carcinma,which is one of the malignant tumors occurring in youth highly,and holds certain proportion in the primary gastric carcinoma.Gastric signet ring cell carcinoma have no special clinical manifestation.It's easy to misdiagnose,and often occupying advanced stage and having metastasis when dignosis.It's insensitive to the chemotherapy,and the prognosis misses extremely,its natural course is only 3～6 months.Gastric signet ring cell carcinoma is a kind of malignant tumor with low difference,strong invasiveness,ability to grow in the stomach wall easily,quick progress speed,high transferability,difficulty to diagnosis and a bad prognosis,thus, its special clinical character,the biological character and behavior,the treatment and prognosis,and so on,revokes our attention.
5-Fu,AMD,DDP,L-OHP,CPT-11,VP-16 and so on is commonly used in the chemotherapy treatment of gastric carcinoma,in which the 5-Fu/platinum union chemotherapy are most commonly used.However the primary or acquired tumor insensitive to gastric carcinoma often affect the chemotherapy effect frequently,and is one of the most common and difficult clinical problems in antineoplastic therapy.The excision repair complementary gene(ERCC1),thymidylate synzyme(TS),the Glutathione-S-transferases(GST-π)is loosely correlating with gastric carcinoma treatment and the prognosis.The high expression of ERCC1 with L-OHP,DDP based chemotherapy curative effect is inverse correlation,but to patients without chemotherapy,the ERCC1 high expression is beneficial in the lifetime target.The relationship between ERCC1 and the lifetime still has dispute;The expression of TS in gastric carcinoma and the resistance to 5-FU still has dispute,the majority research thought the TS expression and 5-FU resistance is correlated,and inverse correlation with the lifetime.TS is a bad prognosis target,but also had research which thinks primary expression of TS can not forecast the later curative effect to gastric carcinoma with 5-Fu based chemotherapy;Some researchs indicate that GST-πcan be a predictor for early gastric carcinoma.High expression of GST-πin gastric carcinoma patient is insensitive not only to platinum,but to ADM,5-Fu,MMC,CBP,indicated GSTs-πplay an important role in the multidrug resistance to tumors.This article plans to observe the expression of ERCC1,TS,GST-πin gastric signet ring cell carcinoma and adencarcinoma,to analyze the expression of ERCC1,TS,GST-πin gastric signet ring cell carcinoma and adencarcinoma and its clinical significance,which will benefit us to make good choice in the chemotherapy of gastric signet ring cell carcinoma and adencarcinoma.
METHODS:Using immunohistochemistry staining method(the S-P law), with special ERCC1,TS,GST-πmonoclonal antibodies,examines the expression of ERCC1、TS and GST-πin 61 gastric signet ring cell carcinoma and 60 adencarcinoma.Statistical analysis was done by SPSS 13.0 and P＜0.05 was considered significant.Analyzing the expression difference in gastric signet ring cell carcinoma and adencarcinoma,and observe their relation to clinical pathology character,the treatment sensitivity and the prognosis in gastric signet ring cell carcinoma and adencarcinoma.
RESULTS:In tumor cells,ERCC1 locates in the cell nucleus,TS locates in the cytoplasma/nucleus,take the expression in the cytoplasma as the positive,GST-πmainly locates in the cytoplasma,the partial cell nuclei also have the expression,take the expression in the cytoplasma as the positive.
In 61 gastric signet ring cell carcinoma,the positive expression rate of ERCC1、TS and GST-πis 25.59%(15/61)、19.67%(12/61)and 54.10%(33/61).In 60 adencarcinoma,the positive expression rate of ERCC1、TS and GST-πis 26.17%(16/60)、38.33%(23/60)and 71.67%(43/60).Between gastric signet ring cell carcinoma and adencarcinoma,the ERCC1 positive expression rate difference has non-significance significance(P＞0.05),while the TS and GST-πpositive expression rate difference has the significance significance(P＜0.05).In gastric signet ring cell carcinoma,difference between the expression of ERCC1,TS,GST-πand patient's sex, the age,drink wine,the pathologic stages,the number of lymph node metastasis has non-significance(P＞0.05),the difference between expression of ERCC1,GST-πand the depth of invasion has statistics significance(P＜0.05).In adenocarcinoma, difference between the expression of ERCC1,TS,GST-πand patient's sex,the age, drink wine,the pathologic stages,the number of lymph node metastasis and the depth of invasion has non-significance(P＞0.05),difference between TS expression and differentiation degree has statistics significance(P＜0.05).In deep invasion(T3-T4) patients,the expression difference of TS,GST-πbetween gastric signet ring cell carcinoma and adencarcinoma has the significance(P＜0.05).
CONCLUSIONS:
1.The expression of ERCC1 in gastric signet ring cell carcinoma and adencarcinoma has no obvious difference,The expression of TS and GST-πin gastric signet ring cell carcinoma is lower than adencarcinoma obviously.
2.The expression of ERCC1,TS,GST-πhas no correlation with patient's sex,the age,drinks wine,the pathology,the number of lymph node metastasis.
3.The expression of ERCC1 and GST-πin gastric signet ring cell carcinoma has correlation with the depth of invasion,the deeper it infiltrates,the lower the expression is.There is no correlation between the expression of ERCC1,TS, GST-πwith the adencarcinoma.
4.In the deep invasion(T3-T4)patients,the expression of TS and GST-πin gastric signet ring cell carcinoma is lower than adencarcinoma.
胃癌是我国常见的消化系肿瘤,严重威胁人类健康。就发病率和死亡率而言,胃癌在我国居恶性肿瘤第二位,治疗原则以手术为主,但是往往在原发肿瘤出现明显症状之前已出现了播散性转移,故多数患者已失去手术机会,而选择以化疗为主的综合治疗。
胃印戒细胞癌是胃癌的一种特殊病理类型,是多发于中青年的高度恶性肿瘤之一,在原发性胃癌中占有一定比例。胃印戒细胞癌无特异性临床表现,临床上易误诊,就诊时大多已属中晚期,有广泛侵袭和转移,特别是难以控制的远处脏器转移,且对放化疗均不敏感,预后极差,其自然病程仅为3～6个月。胃印戒细胞癌是一类分化差,侵袭力强、多在胃壁内弥漫浸润性生长、进展速度快、易转移、临床表现无特异性、不易早期诊断且预后较差的一类高度恶性肿瘤。因此,其特殊的临床特点、生物学特征与行为、治疗及其预后等倍受人们关注。
常用于治疗胃癌的化疗药物有5-氟尿嘧啶(5-fluorouracil,5-Fu)、阿霉素(Adriamycin,ADM)、顺铂(Cisplatin,DDP)、奥沙利铂(Oxaliplatin,L-OHP)、伊立替康(Irinotecan,CPT-11)、依托泊苷(Etoposide,VP-16),氨甲喋吟(Methotrexate,MTX),紫杉类(Paclitaxel、Docetaxel)等,其中铂类与5-Fu的联合化疗方案,是胃癌化疗最常用的方案。然而肿瘤原发或继发性对化疗药物不敏感常常影响化疗效果,是临床常见而又难以解决的问题之一。切除修复交叉互补基因(ERCC1)、胸苷酸合成酶(TS)、谷胱甘肽S转移酶(GST-π)是与胃癌治疗及预后密切相关的三个指标。已有资料显示胃癌组织ERCC1高表达与以L-OHP、DDP为基础的化疗疗效负相关,而对未接受化疗者,ERCC1高表达是有益于生存期的指标,但ERCC1与生存期的关系仍存在争议;胃癌组织中TS表达与氟尿嘧啶(5-Fu)耐药之间仍存在争议,大多数研究认为TS过表达与5-Fu耐药正相关,与生存期负相关,是胃癌不良预后指标,但也有研究认为原发灶TS的表达情况不能预测晚期胃癌以5-Fu为基础化疗的疗效;有研究显示GST-π可能作为胃癌早期诊断的一项指标,GST-π阳性的胃癌患者不仅对DDP,而且对阿霉素、5—Fu、丝裂霉素、卡铂的敏感性均低,表明GST-π对肿瘤产生多药耐药性起重要作用。本文拟通过观察ERCC1,TS,GST-π在胃印戒细胞癌与普通腺癌中的表达情况,研究ERCC1,TS,GST-π在胃印戒细胞癌与普通胃腺癌中的表达水平的区别及其临床意义,为今后胃印戒细胞癌与普通腺癌的化疗方案的选择提供依据。
方法
采用回顾性分析,应用免疫组织化学染色方法(S-P法),使用特异性ERCC1、TS、GST-π抗体,检测61例胃印戒细胞癌标本和60例普通胃腺癌标本中ERCC1、TS、GST-π三种抗原的表达情况,用SPSS13.0软件包分析它们在胃印戒细胞癌与普通腺癌中表达的差异,以及它们与胃印戒细胞癌及腺癌临床病理特征的关系,进而推测它们与胃印戒细胞癌及腺癌治疗敏感性及预后的关系。
结果
在肿瘤细胞中,ERCC1定位于细胞核,TS定位于细胞浆/核,以细胞浆中表达为阳性,GST-π主要定位于细胞浆中,部分细胞核也有表达,以细胞浆表达为阳性。在61例胃印戒细胞癌病理标本中,ERCC1表达阳性率为25.59%(15/61),TS表达阳性率为19.67%(12/61),GST-π表达阳性率为54.10%(33/61)。在60例胃腺癌病理标本中,ERCC1表达阳性率为26.17%(16/60),TS表达阳性率为38.33%(23/60),GST-π表达阳性率为71.67%(43/60)。二者ERCC1阳性率差异无显著性意义(P＞0.05),TS、GST-π阳性率差异有显著性意义(P＜0.05)。在印戒细胞癌患者中,ERCC1、TS、GST-π的表达与患者的性别、年龄、饮酒、病理分期、淋巴结转移数目无显著性差异(P＞0.05),ERCC1、GST-π的表达与浸润深度的差别有统计学意义(P＜0.05)。在普通腺癌患者中,ERCC1、TS、GST-π的表达与患者的性别、年龄、饮酒、病理分期、淋巴结转移数目、浸润深度、分化程度无显著性差异(P＞0.05)。在深层浸润(T3-T4)的患者中,TS、GST-π的表达在印戒细胞癌与腺癌中的差异有显著性(P＜0.05)。
结论
1.ERCC1的表达在印戒细胞癌与普通腺癌中无明显差别,TS、GST-π在印戒细胞癌中的表达水平明显低于普通腺癌。
2.ERCC1、TS、GST-π的表达与患者的性别、年龄、饮酒、病理分期、淋巴结转移数目无关。
3.印戒细胞癌中ERCC1、GST-π的表达与浸润深度有关,浸润深度越浅ERCC1、GST-π表达率越高;普通腺癌中ERCC1、TS、GST-π的表达均与浸润深度无关。
4.在深层浸润(T3-T4)患者中,印戒细胞癌中TS、GST-π的表达明显低于胃普通腺癌。
BACKGROUND AND OBJECTIVE:Gastric carcinoma is a common gastrointestinal carcinoma in our country,which threatens the human health seriously,and its mobility and mortality ranks the second in all kinds of the malignant tumor.The treatment principle is the surgery primarily,but usually it metabasis before dignosis,therefore most has lost the surgery opportunity,and chose the chemotherapy based complex therapy.
Gastric signet ring cell carcinoma is a special pathological type of the gastric carcinma,which is one of the malignant tumors occurring in youth highly,and holds certain proportion in the primary gastric carcinoma.Gastric signet ring cell carcinoma have no special clinical manifestation.It's easy to misdiagnose,and often occupying advanced stage and having metastasis when dignosis.It's insensitive to the chemotherapy,and the prognosis misses extremely,its natural course is only 3～6 months.Gastric signet ring cell carcinoma is a kind of malignant tumor with low difference,strong invasiveness,ability to grow in the stomach wall easily,quick progress speed,high transferability,difficulty to diagnosis and a bad prognosis,thus, its special clinical character,the biological character and behavior,the treatment and prognosis,and so on,revokes our attention.
5-Fu,AMD,DDP,L-OHP,CPT-11,VP-16 and so on is commonly used in the chemotherapy treatment of gastric carcinoma,in which the 5-Fu/platinum union chemotherapy are most commonly used.However the primary or acquired tumor insensitive to gastric carcinoma often affect the chemotherapy effect frequently,and is one of the most common and difficult clinical problems in antineoplastic therapy.The excision repair complementary gene(ERCC1),thymidylate synzyme(TS),the Glutathione-S-transferases(GST-π)is loosely correlating with gastric carcinoma treatment and the prognosis.The high expression of ERCC1 with L-OHP,DDP based chemotherapy curative effect is inverse correlation,but to patients without chemotherapy,the ERCC1 high expression is beneficial in the lifetime target.The relationship between ERCC1 and the lifetime still has dispute;The expression of TS in gastric carcinoma and the resistance to 5-FU still has dispute,the majority research thought the TS expression and 5-FU resistance is correlated,and inverse correlation with the lifetime.TS is a bad prognosis target,but also had research which thinks primary expression of TS can not forecast the later curative effect to gastric carcinoma with 5-Fu based chemotherapy;Some researchs indicate that GST-πcan be a predictor for early gastric carcinoma.High expression of GST-πin gastric carcinoma patient is insensitive not only to platinum,but to ADM,5-Fu,MMC,CBP,indicated GSTs-πplay an important role in the multidrug resistance to tumors.This article plans to observe the expression of ERCC1,TS,GST-πin gastric signet ring cell carcinoma and adencarcinoma,to analyze the expression of ERCC1,TS,GST-πin gastric signet ring cell carcinoma and adencarcinoma and its clinical significance,which will benefit us to make good choice in the chemotherapy of gastric signet ring cell carcinoma and adencarcinoma.
METHODS:Using immunohistochemistry staining method(the S-P law), with special ERCC1,TS,GST-πmonoclonal antibodies,examines the expression of ERCC1、TS and GST-πin 61 gastric signet ring cell carcinoma and 60 adencarcinoma.Statistical analysis was done by SPSS 13.0 and P＜0.05 was considered significant.Analyzing the expression difference in gastric signet ring cell carcinoma and adencarcinoma,and observe their relation to clinical pathology character,the treatment sensitivity and the prognosis in gastric signet ring cell carcinoma and adencarcinoma.
RESULTS:In tumor cells,ERCC1 locates in the cell nucleus,TS locates in the cytoplasma/nucleus,take the expression in the cytoplasma as the positive,GST-πmainly locates in the cytoplasma,the partial cell nuclei also have the expression,take the expression in the cytoplasma as the positive.
In 61 gastric signet ring cell carcinoma,the positive expression rate of ERCC1、TS and GST-πis 25.59%(15/61)、19.67%(12/61)and 54.10%(33/61).In 60 adencarcinoma,the positive expression rate of ERCC1、TS and GST-πis 26.17%(16/60)、38.33%(23/60)and 71.67%(43/60).Between gastric signet ring cell carcinoma and adencarcinoma,the ERCC1 positive expression rate difference has non-significance significance(P＞0.05),while the TS and GST-πpositive expression rate difference has the significance significance(P＜0.05).In gastric signet ring cell carcinoma,difference between the expression of ERCC1,TS,GST-πand patient's sex, the age,drink wine,the pathologic stages,the number of lymph node metastasis has non-significance(P＞0.05),the difference between expression of ERCC1,GST-πand the depth of invasion has statistics significance(P＜0.05).In adenocarcinoma, difference between the expression of ERCC1,TS,GST-πand patient's sex,the age, drink wine,the pathologic stages,the number of lymph node metastasis and the depth of invasion has non-significance(P＞0.05),difference between TS expression and differentiation degree has statistics significance(P＜0.05).In deep invasion(T3-T4) patients,the expression difference of TS,GST-πbetween gastric signet ring cell carcinoma and adencarcinoma has the significance(P＜0.05).
CONCLUSIONS:
1.The expression of ERCC1 in gastric signet ring cell carcinoma and adencarcinoma has no obvious difference,The expression of TS and GST-πin gastric signet ring cell carcinoma is lower than adencarcinoma obviously.
2.The expression of ERCC1,TS,GST-πhas no correlation with patient's sex,the age,drinks wine,the pathology,the number of lymph node metastasis.
3.The expression of ERCC1 and GST-πin gastric signet ring cell carcinoma has correlation with the depth of invasion,the deeper it infiltrates,the lower the expression is.There is no correlation between the expression of ERCC1,TS, GST-πwith the adencarcinoma.
4.In the deep invasion(T3-T4)patients,the expression of TS and GST-πin gastric signet ring cell carcinoma is lower than adencarcinoma.
引文
[1]Bellmunt J,Paz-Ares L,Cuello M et al,Gene expression of ERCCl as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy Ann Oncol 2007,18:522-528.
[2]Metzger R,Leichman CG,Danenberg KD et al,ERCCl mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy.J Clin Oncol 1998,16:309-316.
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[10]周际昌.实用肿瘤内科学,第二版,人民卫生出版社,2003:386.
[11]Johnson NP,Hoeschele JD,Rahn RO.Kinetic analysis of an in vitro binding of radioactive cis-and trans-dichlorodiammineplatinum(II)to DNA.Chem Biol Interact 1980;30:151-169.
[12]Rosell R.Predictive molecular markers in non-small cell lung cancer[J].Curr Opin Oncol,2001,13:101-109.
[13]Yeh KH,Shun CT,Chen CL et al.High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy.Cancer 1998,82:1626-1631.
[14]Choi J,Lim H,Nam DK et al.Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection.Br J Cancer 2001;84:186-192.
[15]Lenz H J,Leichman CG,et al.Thymidylate synthase mRNA level in adenocarcinoma of the stomach:a predictor for primary tumor response and overall survival.J Clin Oncol 1996,14:176-182.
[16]Tew KD.Glutathione-associated enzymes in anticancer drug resistance.Cancer Res 1994,54:4313-4320.
[17]Tsuchida S,Sato K.Glutathione transferases and cancer.Crit Rev Biochem Mol Biol 1992,27:337-384.
[18]周际昌.实用肿瘤内科学,第二版,人民卫生出版社,2003:86-87.
[19]Steven W.Johnson,James P.et al.Cisplatin and Its Analogues[M].Cancer:Principles and Practice of Oncology,6th Edition.Lippincott Williams &Wilkins,USA,2001:380-382.
[20]McHugh PJ,Apanswick VJ,Hartley JA.Repair of DNA interstrand crosslinks:moleculer mechanisms and clinical relevance[J].Lancet Oncol,2001,2:483-490.
[21]Kawakami K,Watanabe G Identification and functional analysis of single nucleotide polymorphim in the tandem repeat sequence of thymidylate synthase[J].Gene Cancer Res,2003,63:6004-6007.
[22] Kweekel DM ,Gelderblom H ,Guchelaar HJ . Pharmacology of oxali2 platin and the use of phamacogenomics to individualize therapy[J ] .Cancer Treat Rev ,2005 ,31 (2):90-105.
[23] Wood RD.Nucleotide excision repair in mammalian cells.J Boil Chem, 1997,272(38):23465-23468.
[24] Adriaan B H. Suzanne Rademakers ,Alex L N ,et al. Action of DNA repair endonuclease ERCC1/ XPF in living cells[J]. Science ,1999 ,284 :958 - 961.
[25] Nunez F ,Chipchase MD,Clarke AR,et al.Nucletide excision repair gene in liver binucleation:the role of P53 and P21.FASEBJ.2000,14:1073-1082.
[26] Dunkern TR,Kaina B .Cell proliferation and DNA breaks are involved in ultraviolet light-reduced apoptosis in nucleotide excision repair-deficient C hinese hamster cell.Mol Biol Cell, 2002, 13(1):348-361.
[27] Wood RD. [ J ]. J Biol Chem, 1997 ,272 :23465-23468.
[28] Shivji MKK, Kenny MK, Wood RD. Proliferating cell nuclear antigen is required for DNA excision repair [J ]. Cell ,1992 ,69 : 367 - 374.
[29] Lehmann AR. Workshop on Eukaryotic DNA repair genes and gene products[J].CancerRes,1995,55:968-970
[30] Park CH, Bessho T, Matsunaga T, Sancar A. Purification and characterization of the XPF-ERCC1 complex of human DNA repair excision nuclease. J Biol Chem 1995;270:22657-60.
[31] Vanduin M , Kiken MHM , Van den TOL J , et al. Genomic characterization of the human DNA excision repair gene ERCC1 [J ] . Nucleic Acids Res, 1987, 15:9195-9213.
[32] Vanduin M , DE WIT J , Odijk H , et al. Molecular characterization of the human excision repair gene ERCC - 1 :cDNA cloning and amino acid homology with the yeast repair gene RAD10[J ]. Cell, 1986 , 44 : 913 - 923.
[33] Sancar A. Mechanisms of DNA excision repair [J ]. Science , 1994 , 266 : 1954- 1956.
[34] Dabholkar M , Vionnet J , Bostick2Bruton F , et ai . Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate wit h response to platinum2based chemot herapy. J Clin Investig ,1994 ,94 (2) :703-708.
[35] Metzger R ,Leichman CG,Danenberg K, et al . ERCC1 mRNA levels complement t hymidylate synt hase mRNA levels in predicting response and survival for gast ric cancer patient sreceiving combination cisplatin and fluorouracil chemot herapy. J Clin Oncol ,1998 ,16 (1) :309-316.
[36] Furuta T , Ueda T , Aune G, et al . Transcription2coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cell . Cancer Res ,2002 ,62 (17) :4899-4902.
[37] Mona Sabo, Camilla Furu Skjelbred, Bjorn Andersen Nexo, et al. Increased mRNA expression levels of ERCCI, OGGI and RAI in colorectal adenomas and carcinomas. BMC Cancer, 2006,6: 20 8 .
[38] 刘晓芳.顺铂对ERCCI 在293 细胞中表达的影响中国公共卫生, 2003, 19(4):441-442.
[39] Amould S ,Hennebelle I ,C anal P, etal .Cellularde terminantso fox aliplatins ensitivityin colon can cerce lllin es.Eu rJ C ancer,20 03,39(1): 112.
[40] MetZger R, Leichman CG,Danenberg KD,et al.ERCClmRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy[J].J Clin Oncol,1998,16(1):309-317 .
[41]. Kwon HC, Roh M, Oh S, Kim SH, Kim M, Kim JS, et al. Prognostic value of expression of ERCCI, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/ oxaliplatin chemotherapy in advanced gastric cancer. Ann Oncol 2007; 18:504-9.
[42] Olaussen KA,Dunant A,Fouret P,et al.DNA repair by ERCCI in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.N Engl J Med, 2006,355(10):983-91.
[43] Codegoni AM,Broggini M,Pitelli MR,et al.Experssion of genes of potential importance in the response to chemotherapy and DNA repair in patients with ovarian cancer.Gynecol Oncol, 1997,65:130-734.
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